RT Journal Article SR Electronic(1) A1 Chen, Chun-Jung A1 Ou, Yen-Chuan A1 Lin, Shih-Yi A1 Raung, Shue-Ling A1 Liao, Su-Lan A1 Lai, Ching-Yi A1 Chen, Shih-Yun A1 Chen, Jian-HongYR 2010 T1 Glial activation involvement in neuronal death by Japanese encephalitis virus infection JF Journal of General Virology, VO 91 IS 4 SP 1028 OP 1037 DO https://doi.org/10.1099/vir.0.013565-0 PB Microbiology Society, SN 1465-2099, AB Japanese encephalitis is characterized by profound neuronal destruction/dysfunction and concomitant microgliosis/astrogliosis. Although substantial activation of glia is observed in Japanese encephalitis virus (JEV)-induced Japanese encephalitis, the inflammatory responses and consequences of astrocytes and microglial activation after JEV infection are not fully understood. In this study, infection of cultured neurons/glia with JEV caused neuronal death and glial activation, as evidenced by morphological transformation, increased cell proliferation and elevated tumour necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6 and RANTES (regulated upon activation, normal T-cell expressed and secreted) production. Replication-competent JEV caused all glial responses and neurotoxicity. However, replication-incompetent JEV lost these abilities, except for the ability to change microglial morphology. The bystander damage caused by activated glia also contributed to JEV-associated neurotoxicity. Microglia underwent morphological changes, increased cell proliferation and elevated TNF-α, IL-1β, IL-6 and RANTES expression in response to JEV infection. In contrast, IL-6 and RANTES expression, but no apparent morphological changes, proliferation or TNF-α/IL-1β expression, was demonstrated in JEV-infected astrocytes. Supernatants of JEV-infected microglia, but not JEV-infected astrocytes, induced glial activation and triggered neuronal death. Antibody neutralization studies revealed that TNF-α and IL-1β, but not RANTES or IL-6, released by activated microglia appeared to play roles in JEV-associated neurotoxicity. In conclusion, following JEV infection, neuronal death was accompanied by concomitant microgliosis and astrogliosis, and neurotoxic mediators released by JEV-activated microglia, rather than by JEV-activated astrocytes, had the ability to amplify the microglial response and cause neuronal death., UL https://www.microbiologyresearch.org/content/journal/jgv/10.1099/vir.0.013565-0